PMP201 Infection ISU: Antibiotics Part 3

PMP201 - Infection ISU: Antibiotics - Drug Classes and Mechanisms - Part 3

• Course: PMP201 Infection ISU
• Topic: Antibiotics - Drug Classes and Mechanisms - Part 3
• Date: 6th November 2024
• Lecturer: Dr. Giulio Nannetti

Previous & Complementary Knowledge

• Health, Disease & Patient (PMP101) 2023/24: Microbiology lectures - Bacteria composition, Bacterial growth.
• Patient-Centred Learning I (PMP201) 2024/25: Overview of antibiotics (1, 2 & 3) from Dr. Guirguis. Chemistry of antibiotics from Dr. Padalino.

Learning Outcomes

• Antimetabolite Antibiotics: Outline the antibacterial mechanism, effect, and properties of the main types.
• Nucleic Acid Synthesis Inhibitors: Outline the antibacterial mechanism, effect, and properties of inhibitors of nucleic acid synthesis.
• Alternative Mechanism Antibiotics: Outline the antibacterial mechanism, effect, and properties of antibiotics acting with an alternative mechanism of action.
• Therapeutic Agents for Tuberculosis: Identify the therapeutic agents for tuberculosis.

Mechanism of Actions - Recap

• Inhibition of Cell Wall Synthesis: ẞ-lactams (penicillins, cephalosporins, monobactams, carbapenems), Glycopeptides (vancomycin).
• Inhibition of Nucleic Acid Synthesis: Fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin), Rifamycins (rifampin).
• Inhibition of Protein Synthesis: Aminoglycosides, Tetracyclines, Macrolides, Lincosamines, Chloramphenicol, Oxazolidinones.
• Acting as Antimetabolites: Primarily targeting key enzymes to block folic acid synthesis (essential for nucleotide production) - Sulphonamides, Trimethoprim.

3) Antibiotic classes acting as antimetabolites

• Inhibit bacterial metabolic pathways (distinct from those in eukaryotic cells)
• Selective toxicity - Primarily target key enzymes to block folic acid synthesis; essential for nucleotide production.
• Bacteriostatic effect.

3a) Sulphonamides

• Sulfamethoxazole mechanism: Folic acid is essential to produce purines (nucleotides). Bacteria cannot uptake folic acid from outside. Bacteria synthesize folic acid, starting from a precursor p-aminobenzoic acid (PABA). Sulphonamides act by competing with PABA to inhibit the first enzyme dihydropteroate synthase (DHPS). In human body - Folic acid (Vitamin B9) obtained in the diet.

3b) Trimethoprim

• Trimethoprim mechanism: Trimethoprim targets dihydrofolate reductase (DHFR). DHFR is present in human cells, for the dietary folic acid activation. Selective toxicity: Trimethoprim has 100,000x higher affinity for bacterial DHFR over human counterpart.

3a+b) Sulphonamides + trimethoprim (co-trimoxazole)

• Sequential blocking mechanism: Both drugs block the folic acid synthesis at two distinct steps → potential synergistic effect.
• Bacteriostatic effect.
• Spectrum: Broad (Gram+ve and Gram-ve).

3a+b) Sulphonamides + trimethoprim (co-trimoxazole) - Side effects/Contraindications/Cautions

• Side effects: Risk of folate deficiency (during pregnancy, associated with neural tube defects), Hyperkalaemia, Hypersensitivity (rash and anaphylaxis)
• Contraindications: Avoid in first-trimester of pregnancy, patients with blood dyscrasias, in acute porphyria, elderly, neonates, and predisposition to folate deficiency.

4) Inhibition of nucleic acids synthesis

• DNA synthesis: Fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin).
• RNA synthesis: Rifamycins (rifampicin)

4a) Fluoroquinolones

• Mechanism: Inhibit DNA replication by interfering with bacterial topoisomerases (2 types). DNA gyrase (not present in humans) is targeted. Topoisomerase IV (human enzyme) is inhibited at high doses.
• Spectrum: Broad (effective against Gram +ve and -ve).
• Uses: Serious RTIs (CAP), skin/soft tissue infections, and UTIs (E. coli). Systemic fluoroquinolones must be prescribed when other options are inappropriate.
• Side Effects: GI distress, tendonitis, tendon rupture, muscle weakness, joint pain, prolonged QT interval, aortic aneurysm (rare), seizures (rare), peripheral neuropathy).
• Contraindications/Cautions: Patients with history of tendon damage, taking corticosteroids, QT prolongation risk factors, in epilepsy, psychiatric disorders, or patients with renal impairment, exposure to sunlight.

4b) Rifamycins (Rifampicin)

• Mechanism: Inhibits the initiation of bacterial DNA transcription by blocking bacterial RNA polymerase activity.
• Bactericidal effect.
• Spectrum: Broad (Gram +ve and -ve), and Mycobacteria.
• Uses: Tuberculosis, N. meningitidis/H. influenzae meningitis (enters cerebrospinal fluid).
• Side Effects: GI distress, minor hepatotoxicity, discoloration of body fluids (urine and sweat turn orange - harmless), many interactions (inducing cytochrome P450).
• Contraindications: Patients with acute porphyrias.

5) Alternative mechanisms

• Nitroimidazoles (Metronidazole): Generates unstable metabolites leading to DNA fragmentation, Bactericidal effect.
• Nitrofurantoin: Generates reactive free radicals, interfering with RNA, DNA and other components synthesis. Bactericidal effect.

5a) Nitroimidazoles (Metronidazole)

• Mechanism: Generating free radicals in bacteria. Reduced form generates an unstable nitroso radical metabolite (ROS). ROS leads to DNA fragmentation.
• Spectrum: Only anaerobes (including protozoa). Activated/reduced by low redox potential within cells.
• Uses: Treat infections of anaerobic bacteria, H. pylori eradication
• Side Effects: Gastrointestinal distress, metallic taste, furred tongue, peripheral neuropathy (rare), disulfiram-like adverse reactions with alcohol.
• Cautions: Avoid exposure to sunlight with topical use, avoid intravaginal preparations in young girls, and avoid alcohol.

5b) Nitrofurantoin

• Mechanism: Generating reactive free radicals; interfering with RNA, DNA and other components synthesis.
• Spectrum: Effective against most Gram +ve and some Gram -ve (E. coli).
• Uses: Treat and prevent uncomplicated acute UTIs.
• Side effects: Discoloration of body fluids (urine and sweat), pulmonary toxicity (fever, chills, cough), peripheral neuropathy (rare), blood disorders (rare).
• Contraindications: Decreased renal function (eGFR < 45 mL/min), G6PD deficiency, infants (less than 3 months old). In anaemia, diabetes, electrolyte imbalances, and folate deficiency.

Treatment for Tuberculosis (TB)

• 10.6 million people fell ill with TB in 2021, 1.6 million died.
• Types of TB: Pulmonary (infection in the lungs) or Extrapulmonary (spread to other organs). Latent (asymptomatic) and Active (symptomatic).
• Mycobacterium tuberculosis: Gram+ve, aerobe, complex and unique cell wall. Important virulence factors, markers (acid-fast/auramine fluorescent staining (mycolic acids)).
• Cell Wall of Mycobacteria: Thick, hydrophobic, robust and waxy (variety of lipids); hydrophobic barrier to antibiotics.
• Treatment for TB: First-line drugs (RIPE): Rifampicin (RNA polymerase inhibitor), Isoniazid (inhibitor of mycolic acids synthesis), Pyrazinamide (interferes with fatty acid synthesis), and Ethambutol (interferes with arabinogalactans synthesis).
• Newly diagnosed/re-treatment therapies: Different protocols based on the stage (initial phase and continuation).
• Drug-resistant strains: Multidrug-resistant TB (MDR-TB) and Extensively drug-resistant TB (XDR-TB).

Quiz Questions

• Trimethoprim target: Folic acid synthesis.
• Not a first-line TB drug: Amoxicillin.

This quiz covers the mechanisms and effects of various classes of antibiotics, focusing on antimetabolite antibiotics, nucleic acid synthesis inhibitors, and alternative mechanism antibiotics. Designed for students of the PMP201 Infection ISU course, it reinforces key concepts essential for understanding antibiotic actions in clinical settings.